Synthesis of Somatostatin Mimetics Based on the 1-Deoxymannojirimycin Scaffold Sebastien G. Gouin and Paul V. Murphy* Centre for Synthesis and Chemical Biology, UCD School of Chemistry and Chemical Biology, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
[email protected] Received July 14, 2005
A novel synthesis of somatostatin mimetics based on the 1-deoxymannojirimycin (DMJ) scaffold has been developed. This involved development of a route suitable for the strategic grafting of pharmacophoric tryptophan and lysine side chains to the nitrogen atom of the piperidine ring and to the primary hydroxyl group of DMJ, respectively. The novel peptidomimetics were found to bind with higher affinity to sst4 receptors than to sst5 receptors.
1. Introduction There has been recent progress in the application of pyranosides and related scaffolds as platforms for drug discovery since the first experimental application by researchers at the University of Pennsylvania, which showed that novel ligands (peptide β-turn mimetics) for peptide hormone receptors could be developed based on β-D-glucopyranose.1 In this example, pharmacophoric groups, which correspond to amino acid side chains, were grafted to the pyranose, which acted as a replacement for the peptide backbone. Interest in this area has since extended2 to the wider application of pyranosides as peptidomimetics3 and as scaffolds for the solid-phase synthesis of prospecting combinatorial libraries.4 There has been interest in syntheses of pyranose-based sugar amino acids (SAAs)5 and incorporation of such motifs into molecules of biological interest. Investigations have included (amino)sugar scaffolds, including L-sugars,6 (1) (a) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Salvino, J.; Leahy, E. M.; Sprengeler, P. A.; Furst, G.; Smith, A. B., III; Strader, C. D.; Cascieri, M. A.; Candelore, M. R.; Donaldson, C.; Vale, W.; Maechler, L. J. Am. Chem. Soc. 1992, 114, 9217. (b) Nicolaou, K. C.; Salvino, J. M.; Raynor, K.; Pietranico, S.; Reisine, T.; Freidinger, R. M.; Hirschmann, R. In Peptides - Chemistry, Structure, and Biology, Proceedings of the 11th American Peptide Symposium; Rivier, J. E., Marshall, G. R., Eds.; ESCOM: Leiden, 1990; pp 881-884. (c) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Leahy, E. M.; Salvino, J.; Arison, B.; Cichy, M. A.; Spoors, P. G.; Shakepseare, W. C.; Sprengler, P. A.; Hamley, P.; Smith, A. B.; Reisine, T.; Raynor, K.; Maechler, L.; Donaldson, C.; Vale, W.; Freidinger, R. M.; Cascieri, M. R.; Strader, C. D. J. Am. Chem. Soc. 1993, 115, 12550.
sugar amino acids,7 and disaccharides.8 Although no drug has yet been developed, potent ligands for receptors have been identified9 and it has been shown that pyranoside derivatives can have improved cellular permeability over (2) For reviews of sugar scaffolds see: (a) Sofia, M. J. Mol. Diversity 1998, 3, 75. (b) Sofia, M. J. Med. Chem. Res. 1998, 8, 362. (c) Sofia, M. J.; Silva, D. J. Curr. Opin. Drug Discov. Dev. 1999, 2, 365. (d) Schweizer, F.; Hindsgaul, O. Curr. Opin. Chem. Biol. 1999, 3, 29. (e) Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev. 2002, 102, 491. (f) Schweizer, F. Angew. Chem., Int. Ed. 2002, 41, 231. (g) Marcaurelle, L. A.; Seeberger, P. H. Curr. Opin. Chem. Biol. 2002, 6, 289. (h) Chakraborty, T. K.; Srinivasu, P.; Tapadar, S.; Mohan, B. K. J. Chem. Sci. 2004, 116, 187. (i) Schweizer, F. Trends Glycosci. Glycotechnol. 2003, 15, 315. (3) The first nonpeptidal peptidomimetic was reported in 1986, which recognized the opiate receptor for which it was designed. See: Belanger, P. C.; Dufresne, C. Can. J. Chem. 1986, 64, 1514. (4) (a) Wunberg, T.; Kallus, C.; Opatz, T.; Henke, S.; Schmidt, W.; Kunz, H. Angew. Chem., Int. Ed. 1998, 37, 2503. (b) Sofia, M. J.; Hunter, R.; Chan, T. Y.; Vaughan, A.; Dulina, R.; Wang, H. M.; Gange, D. J. Org. Chem. 1998, 63, 2802. (c) Jain, R.; Kamau, M.; Wang, C.; Ippolito, R.; Wang, H.; Dulina, R.; Anderson, J.; Gange, D.; Sofia, M. Bioorg. Med. Chem. Lett. 2003, 13, 2185. (d) Opatz, T.; Kallus; C.; Wunberg, T.; Schmidt, W.; Henke, S.; Kunz, H. Carbohydr. Res. 2002, 337, 2089. (e) Opatz, T.; Kallus, C.; Wunberg, T.; Schmidt, W.; Henke, S.; Kunz, H. Eur. J. Org. Chem. 2003, 1527. (f) Opatz, T.; Kallus, C.; Wunberg, T.; Kunz, H. Tetrahedron 2004, 60, 8613. (5) (a) Graf von Roedern, E.; Kessler, H. Angew. Chem., Int. Ed. Engl. 1994, 33, 670. (b) Kessler, H.; Diefenbach, B.; Finsinger, D.; Geyer, A.; Gurrath, M.; Goodman, S. L.; Holzemann, G.; Haubner, R.; Jonczyk, A.; Muller, G.; Graf von Roedern, E.; Wermuth, J. Lett. Pept. Sci. 1995, 2, 155. (6) Hirschmann, R.; Cichy-Knight, M. A.; van Rijn, R. D.; Sprengler, P. A.; Spoors, P. G.; Shakespeare, W. C.; Pietranico-Cole, S.; Barbosa, J.; Liu, J.; Yao, W.; Roher, S.; Smith, A. B., III. J. Med. Chem. 1998, 41, 1382. (7) Graf von Roedern, E.; Lohof, E.; Hessler, G.; Hoffmann, M.; Kessler, H. J. Am. Chem. Soc. 1996, 118, 10156.
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peptides.10 Both of these are objectives for peptidomimetic research.11 Progress is continually dependent on advances in synthetic carbohydrate chemistry both in solution and on solid phase. These include the development of orthogonal protecting group strategies, strategies for regioselective manipulation of pyranoside hydroxyl groups, and the chemoselective manipulation of functional groups. The application of iminosugar-based scaffolds as peptidomimetics has been less well-developed although some work has been carried out by Le Merrer and co-workers12 and, more recently, by researchers from our group. 13 This is presumably because such scaffolds are not as readily available as pyranosides and the synthesis of iminosugars is not trivial.14 Iminosugars themselves have been of significant interest as glycosidase inhibitors15 and some have found clinical use.16 The use of iminosugars as scaffolds for bioorganic and medicinal chemistry offers the possibility, not available to pyranosides, of incorporating a charged hydrogen bond donor through protonation of the ring nitrogen atom which would occur at physiological pH. In addition, pharmacophoric groups can be grafted to the nitrogen atom. Herein we describe an approach to the synthesis of somatostatin mimetics derived from 1-deoxymannojirimycin. 2. Results and Discussion 2.1. Design of Somatostatin Mimetics. Somatostatin is a cyclic peptide that regulates the release of growth hormone and other pituitary hormones and plays a role in neuronal transmission. A number of receptor subtypes for this hormone have been identified. The somatostatin antagonist 1, developed by Hirschmann and (8) For some recent syntheses of disaccharide libraries see: (a) Sofia, M. J.; Allanson, N.; Hatzenbuhler, N. T.; Jain, R.; Kakarla, R.; Kogan, N.; Liang, R.; Liu, D. S.; Silva, D. J.; Wang, H. M.; Gange, D.; Anderson, J.; Chen, A.; Chi, F.; Dulina, R.; Huang, B. W.; Kamau, M.; Wang, C. W.; Baizman, E.; Branstrom, A.; Bristol, N.; Goldman, R.; Han, K. H.; Longley, C.; Midha, S.; Axelrod, H. R. J. Med. Chem. 1999, 42, 3193. (b) Baizman, E. R.; Branstrom, A. A.; Longley, C. B.; Allanson, N.; Sofia, M. J.; Gange, D.; Goldman, R. C. Microbiology-SGM 2000, 146, 3129. (c) Castoldi, S.; Cravini, M.; Micheli, F.; Piga, E.; Russo, G.; Seneci, P.; Lay, L. Eur. J. Org. Chem. 2004, 2853. (d) Venot, A.; Swayze, E. E.; Griffey, R. H. Boons, G.-J. ChemBioChem 2004, 5, 1228. (9) Prasad, V.; Birzin, E. T.; McVaugh, C. T.; van Rijn, R. D.; Rohrer, S. P.; Chicci, G.; Underwood, D. J.; Thornton, E. R.; Smith, A. B., III; Hirschmann, R. J. Med. Chem. 2003, 46, 1858. (10) El Oualid, F.; Burm, B. E. A.; Leroy, I. M.; Cohen, L. H.; van Boom, J. H.; van den Elst, H.; Overkleeft, H. S.; van der Marel, G. A.; Overhand, M. J. Med. Chem. 2004, 47, 3920. (11) Hirschmann, R. Angew. Chem., Int. Ed. Engl. 1991, 30, 1278. (12) (a) Le Merrer, Y.; Poitout, L.; Depezay, J.-C.; Dosbaa, I.; Geoffroy, S.; Foglietti, M.-J. Bioorg. Med. Chem. Lett. 1997, 6, 11667. (b) Le Merrer, Y.; Poitout, L.; Depezay, J.-C. In Methods in Molecular Medicine: Peptidomimetics Protocols. Kazmierski., W. M., Ed.; Humana Press Inc.: Totowa, NJ, 1999; Vol. 23. (13) (a) Chery, F.; Murphy, P. V. Tetrahedron Lett. 2004, 45, 2067. (b) Chery, F.; Cronin, L.; O’ Brien, J. L.; Murphy, P. V. Tetrahedron 2004, 60, 6597. (14) For a recent review on synthesis of iminosugars containing sixmembered rings see: Afarinkia, K.; Bahar, A. Tetrahedron Asymmetry 2005, 16, 1239. (15) For reviews on glycosidase inhibition by iminosugars and related compounds see: (a) Hughes, A. B.; Rudge, A. J. Nat. Prod. Rep. 1994, 135. (b) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2, 199. (c) Ganem, B. Acc. Chem. Res. 1996, 29, 340. (d) Heightman, T. D.; Vasella A. T. Angew. Chem., Int. Ed. 1999, 38, 750. (e) Lillelund V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. Rev. 2002, 102, 515. (f) Greimel, P.; Spreitz, J.; Stutz, A. E.; Wrodnigg, T. M. Curr. Top. Med. Chem. 2003, 3, 513. (g) Asano, N.; Nash R. J.; Molyneaux, R. J.; Fleet, G. W. J. Tetrahedron Asymmetry 2000, 11, 1645. (16) Kingma, P. J.; Menheere, P. P.; Sels, J. A.; Nieuwenhuijzen Kruseman, A. C. Diabetes Care 1992, 15, 478.
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CHART 1
co-workers, is based on the β-D-glucopyranoside scaffold (Chart 1). We proposed the working out of a synthesis of 2, a structural analogue of 1, from 1-deoxymannojirimycin (DMJ) scaffold. This required the development of a strategy for grafting the pharmacophoric tryptophan and lysine side chains to the nitrogen atom of the piperidine ring and to the primary hydroxyl group, respectively. The piperidine 2 lacks the benzyl groups found in 1 and in iminosugars synthesized by Le Merrer. The branching positions on the scaffold would lead to a different spatial distance between the indole and pentylamino groups. 2.2. Synthesis of Somatostatin Mimetics. The synthesis of 2 commenced from 3 which was prepared, as previously described,17 from DMJ.18,19 Preliminary efforts to introduce a TIPS or TBDPS group on the primary hydroxyl group of 3 were unsuccessful. However, the reaction of 3 in acetone using a catalytic amount of PPTS gave, in a regioselective manner, 4 in 70% yield.20 The formation of the diacetonide 5 was also observed; the yield of 5 varied from 2 to 10% in a number of experiments. The TBS group was then introduced regioselectively at the primary hydroxyl group to give 6 using TBSCl and imidazole in DMF. The introduction of the benzyl or methoxyphenylmethyl (MPM) protecting at the remaining free hydroxyl group of 6 was not achieved in our hands; however, the MOM protecting group was introduced to this hydroxyl group by the reaction of 6 with MOMCl, diisopropylethylamine (DIPEA) in dichloromethane giving 7 in 89% yield (Scheme 1). Conditions for the regioselective removal of protecting groups from 7 were investigated next (Scheme 2). It was possible to remove the TBS protecting group using TBAF in THF to give 9; however, the yield was only 47%. This was due to the basicity of the TBAF, which led to the removal of the CBz group as well. Indeed it has recently been shown that TBAF can remove carbamate protecting groups.21 The removal of the TBS group was, however, achieved in a selective fashion using HF-pyridine and 9 was obtained in 75% yield after 18 h. Selective deprotection of the CBz group by stirring a mixture of 7 and Pd-C in THF in the presence of H2 gave 8 in a quantitative yield. Grafting of the alkylamino side chain to the primary hydroxyl group of 9 was explored next. The triflate 12 (17) Paulsen, H.; Matzke, M.; Orthen, B.; Nuck, R.; Reutter, W. Liebigs Ann. Chem. 1990, 953. (18) For a synthesis of DMJ from our own group see: O’Brien J. L.; Tosin, M.; Murphy, P. V. Org Lett. 2001, 3, 3353. (19) For a five-step synthesis of DMJ from D-fructose see: Spreitz, J.; Stu¨tz, A. E.; Wrodnigg, T. Carbohydr. Res. 2002, 337, 183. (20) Schueller, A. M.; Heiker, F. R.; Bayer, A.-G. Carbohydr. Res. 1990, 203, 308. (21) Jacquemard, U.; Be´ne´teau, V.; Lefoix, M.; Routier, S.; Me´rour, J.-Y.; Coudert, G. Tetrahedron 2004, 60, 10039.
Synthesis of Somatostatin Mimetics SCHEME 1
SCHEME 4
SCHEME 2
SCHEME 3
was first prepared from phthalamide derivative 111c and attempts to use this as an electrophile in reactions with 9 were unsuccessful. The attempted reaction of 12 with 9 in the presence of sodium hydride led to formation of the cyclic carbamate 1422 which occurs via 13 (Scheme 3). Attempts to effect the desired alkylation reaction of 12 in absence of base were not successful. (22) For a previous observation of a related cyclic carbamate see: Fellows, L. E.; Bell, E. A.; Lynn, D. G.; Pilkiewicz, F.; Miura, I.; Nakanishi, K. J. Chem. Soc., Chem. Commun. 1979, 977.
The azide derivative 15 was freshly prepared as described previously,1c,6 and the alkylation of 9 with this electrophile in dichloromethane gave 16 in 77% yield. This experiment was conducted in absence of base and under vacuum, according to the protocol previously described by Hirschmann and co-workers.6 The CBz group was removed in the presence of the azide group and the other protecting groups by heating 16 in ethanolic potassium hydroxide to give 17. The triflate 19, freshly prepared from its alcohol precursor 18,1c on reaction with 17 in the presence of sodium hydride gave the indole derivative 20 in 47% yield (Scheme 4). Next, the benzensulfonyl group was removed from 20 by heating in the presence of 5 M aqueous NaOH-EtOH; the azide was converted to the amine using catalytic hydrogenation to give 21. The MOM and isopropylidene groups were finally removed under acidic conditions to give the target compound 2 (Scheme 5). 2.3. Biological Evaluation. Compounds 2 and 21 were investigated for their effects in an in vitro nonselective sst receptor binding assay23 and in in vitro selective sst424 and sst525 receptor binding assays. The results are summarized in Table 1. In the nonselective assay the Ki values determined for 2 and 21 were 26 and 21 µM, respectively. Both iminosugar derivatives showed preferential binding to sst4 receptors than to sst5 receptors. Compounds 2 and 21 inhibited binding of the control to sst4 receptors by 46% and 48% (both at 1.0 µM), respectively, whereas they did not show any binding to sst5 receptors at this concentration, and only displayed significant inhibition of the binding at 1.0 × 10-4 M. (23) Brown, P. J.; Lee, A. B.; Norman, M. G.; Presky, D. H.; Schonbrunn, A. J. Biol. Chem. 1990, 265, 17995. (24) Rohrer, L.; Raulf, F.; Bruns, C.; Buettner, R.; Hofstaedter, F.; Schu¨le, R. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 4196. (25) Yamada, Y.; Kagimoto, S.; Kubota, A.; Yasuda, K.; Masuda, K.; Someya, Y.; Ihara, Y.; Li, Q.; Imura, H.; Seino, S. Biochem. Biophys. Res. Commun. 1993, 195, 844.
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TABLE 1. Binding of Iminosugar Derivatives at Somatostatin Receptors
compd
sst (nonspecific) Ki (µM)
sst4 (% inhibition at 1.0 × 10-6 M)
sst5 (% inhibition at 1.0 × 10-6 M)
sst5 (% inhibition at 1.0 × 10-5 M)
sst5 (% inhibition at 1.0 × 10-4 M)
2 21
26 21
46 48
